In most mammalian tissues, homeostasis is maintained by tissue stem cells that function through continued self-renewal and differentiation. Despite the importance of this cell fate decision to tissue homeostasis, the general rules by which stem cell progeny commit to the paths of self- renewal or differentiation are largely unknown. Most current paradigms presume that environmental cues determine the fate of individual stem cell progeny. Unexpectedly, our preliminary data and published studies show that rodent spermatogonial stem cell (SSC) progeny autonomously elicit self-renewal and differentiation in a stochastic manner with constant probability, and that this balance may be regulated by extrinsic cues. These findings point to new mechanisms guiding mammalian SSC self-renewal and differentiation, which will likely prove relevant to other stem cell types. Here w propose to investigate the physiological regulation and the molecular components governing mouse SSC stochastic fate choice. Specifically, we will examine the role of specific internal and external factors that can influence fate choice of SSC progeny and identify novel SSC intrinsic factors that promote self-renewal through a genetic screen. Insights from this study may provide the basis for new therapeutic interventions that restore fertility and optimize birth control.